Methods and formulations for modulating the human sexual response

ABSTRACT

The invention is directed to improved methods for modulating the human sexual response by administering an oral formulation of phentolamine to the blood circulation thereby modulating the sexual response on demand.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.08/431,145 now U.S. Pat. No. 5,731,339, filed on Apr. 28, 1995, and fromwhich priority under 35 USC §120 is claimed.

FIELD OF THE INVENTION

The application is directed to improved formulations for theadministration of vasodilator agents to the blood circulation of a humanin order to modulate the human sexual response on demand.

BACKGROUND OF THE INVENTION

The human sexual response in both males and females results from acomplex interplay of psychological, hormonal, and other physiologicalinfluences. One important aspect of human sexual response that is commonto both men and women is the erectile response which itself results froman interplay between the autonomic nervous system, the endocrine system,and the circulatory system.

Failure of the erectile response is most common in men and is referredto as impotence. Impotence is the inability of a male to achieve orsustain a penile erection sufficient for vaginal penetration andintercourse. Numerous approaches have been taken in attempts to treatimpotence. These approaches include the use of external or internallyimplanted penile prosthesis. (See, e.g., U.S. Pat. No. 5,065,744, toZumanowsky). A variety of drugs and methods for administering drugs havealso been used in attempts to treat impotence. For example, U.S. Pat.No. 3,943,246 to Sturmer addresses treatment of impotence in men bybuccal and peroral administration of daily doses of 300-1500international units (I.U.) of oxytocin or daily divided doses of 150-250I.U. of desamino-oxytocin. The patent states that the buccaladministration of 100 I.U. three times a day for 14 days results inimprovement of impotentia erections in 12 of the 16 patients treated.

U.S. Pat. No. 4,530,920 to Nestor et al. suggests the possibility thatadministration of nonapeptide and decapeptide analogs of luteinizinghormone releasing hormone agonists may be useful in the induction orenhancement of sexual behavior or therapy for impotence or frigidity.Nestor et al. suggest numerous routes of administration of the analogsincluding buccal, sublingual, oral, parenteral (including subcutaneous,intramuscular, and intravenous administration), rectal, vaginal, andothers.

U.S. Pat. No. 4,139,617 to Grunwell et al. suggests buccal and otherroutes of administration of 19-oxygenated-androst-5-enes for theendocrine mediated enhancement of the libido in humans.

U.S. Pat. No. 4,863,911 to Anderson et al. addresses methods fortreating sexual dysfunction in mammals using a biooxidizable,blood-brain barrier penetrating estrogen derivative. One of thepurported objects of the Anderson et al. invention is the treatment of"psychological impotence" in males. Test results showed that the drugsused in the study stimulated mounting behavior, intromission, and mountlatency in castrated rats.

A number of publications have proposed the use of various vasodilatorsfor the treatment of impotence in males. Attempts to utilizevasodilators for the treatment of impotence were prompted by the factthat a significant percentage of cases of impotence were noted to bevasculogenic, i.e. resulting from vascular insufficiency.

Voss et al., U.S. Pat. No. 4,801,587, issued Jan. 31, 1989, addressesthe use of an ointment containing a vasodilator and a carrier agent fortopical application to the penis of impotent men. The Voss et al. patentalso describes application of such an ointment into the urethra of thepenis using a catheter as well as a multi-step regimen for applying avasodilator to the skin of the penis. In addition, Voss et al. proposesthe surgical removal of a portion of the fibrous sheath surrounding thecorpora cavernosum, thereby facilitating the penetration of avasodilator-containing ointment into the corpora cavernosum.Vasodilators suggested for use by Voss et al. include papaverine,hydralazine, sodium nitroprusside, phenoxybenzamine, and phentolamine.The Voss et al. patent, however, provides no information regarding theactual efficacy of the treatments proposed or the nature of the responseto such treatments.

U.S. Pat. No. 4,127,118 to Latorre describes treating male impotence bydirect injection of the vasodilating drugs into the corpus cavernosumand the corpus spongiosum of the penis using a syringe and one or morehypodermic needles. More particularly, the Latorre patent proposes theintracavernosal and intraspongiosal injection of sympathomimetic aminessuch as nylidrin hydrochloride, adrenergic blocking agents such astolazoline hydrochloride, and direct acting vasodilators such asisoxsuprine hydrochloride and nicotinyl alcohol.

Brindley, G. S. (Br. J. Pharmac. 87:495-500, 1986) showed that, wheninjected directly into the corpus cavernosum using a hypodermic needle,certain smooth muscle relaxing drugs including phenoxybenzamine,phentolamine, thymoxamine, imipramine, verapamil, papaverine, andnaftidrofuryl caused erection. This study noted that injection of an"appropriate dose of phenoxybenzamine or papaverine is followed by anunrelenting erection lasting for hours." Injection of the other drugsstudied induced erections lasting from about 11 minutes to about 6.5hours.

Zorgniotti et al., J. Urol. 133:39-41 (1985) demonstrated that theintracavernosal injection of a combination of papaverine andphentolamine could result in an erection in otherwise impotent men.Similarly, Althof et al. J. Sex Marital Ther. 17(2): 101-112 (1991)reported that intracavernosal injection of papaverine hydrochloride andphentolamine mesylate resulted in improved erectile ability in about 84%of patients injected. However, in that study the dropout rate was 57%,fibrotic nodules developed in 26% of the patients, 30% of the patientsdeveloped abnormal liver function values, and bruising occurred in 19%of the patients.

Other studies describing intracavernosal injection of drugs usinghypodermic needles for the treatment of impotence include: Brindley, J.Physiol. 342:24P (1983); Brindley, Br. J. Psychiatr. 143:312-337 (1983);Virag, Lancet ii:978 (1982); and Virag, et al., Angiology 35:79-87(1984).

While intracavernosal injection may be useful for inducing erections inimpotent men, the technique has numerous drawbacks. Obvious drawbacksinclude pain, risk of infection, inconvenience and interference with thespontaneity of the sex act. Priapism (prolonged and other painfulerection) also appears to be a potential problem when using injectionmethods. See, e.g. Brindley, (1986). Another problem arising in somecases of intracavernosal injection involves the formation of fibroticlesions in the penis. See, e.g., Corriere, et al., J. Urol. 140:615-617(1988) and Larsen, et al., J. Urol. 137:292-293 (1987).

Phentolamine, which has been shown to have the potential to induceerection when injected intracavernosally, has also been the subject oforal administration to test its effects in men having non-specificerectile insufficiency (Gwinup, Ann. Int. Med. 15 July 1988, pp.162-163). In that study, 16 patients ingested either a placebo or a 50mg orally administered dose of phentolamine. Eleven of the 16 patients(including three placebo-treated patients) became tumescent, became moreresponsive to sexual stimulation, and were able to achieve an erectionsufficient for vaginal penetration after waiting 1.5 hours to attemptintercourse.

Sonda et al. J. Sex & Marital Ther. 16(1): 15-21 (year) reported thatyohimbine ingestion resulted in subjective improvement in erectileability in 38% of impotent men treated, but only 5% of the treatedpatients reported complete satisfaction.

Zorgniotti et al, PCT/US94/09048, describes the transmucosaladministration of a variety of vasodilators including phentolaminemesylate for modulating the human sexual response.

Of interest to the background of the invention is the disclosure ofStanley et al., U.S. Pat. No. 4,885,173, which addresses methodsadministering drugs having cardiovascular or renal vascular activitythrough use of a lollipop assertedly facilitating drug absorptionthrough the mucosal tissues of the mouth, pharynx, and esophagus. TheStanley et al. patent proposes that a large number oflollipop-administered drugs may improve cardiovascular functionincluding drugs exhibiting direct vasodilating effects, includingcalcium channel blockers, β-adrenergic blocking agents, serotoninreceptor blocking agents, angina blocking agents, otheranti-hypertensive agents, cardiac stimulating agents, and agents whichimprove renal vascular function.

U.S. Pat. No. 5,059,603 to Rubin describes the topical administration tothe penis of isoxsuprine and caffeine, and nitroglycerine and caffeinealong with suitable carrier compounds for the treatment of impotence.

There continues to exist a need in the art for effective means formodulating human sexual response and especially for enhancing erectileability in males suffering from impotence. Ideally, such means would beconvenient and simple to use, would not require a constant dosageregimen or even multiple doses to achieve desired results, would benon-invasive and would allow a rapid and predictable capacity for onsetof erectile function on demand and in response to normal sexualstimulation.

All of the references set out in this specification are incorporatedherein by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention provides improved formulations for modulating thehuman sexual response in a human by administering a vasodilator agent tothe circulation in an amount effective to increase blood flow to thegenitalia. According to the invention, modulation of male and femalehuman sexual response is provided on demand by administering aneffective vasodilating amount of the agent in an oral formulation.Vasodilating agents useful in the present invention include, but are notlimited to, the group consisting of phentolamine mesylate, phentolaminehydrochloride, phenoxybenzamine, yohimbine, organic nitrates (e.g.nitroglycerin), thymoxamine, imipramine, verapamil, isoxsuprine,naftidrofuryl, tolazoline and papaverine. The presently preferredvasodilator agent is phentolamine mesylate. The presently preferred oralformulation comprises in combination, a vasodilator agent in a rapidlydissolving tablet. Preferred rapidly dissolving tablets have adisintegration time of from about 1 minute to about 10 minutes. Mostpreferred are rapidly dissolving tablets having the disintegration timesof less than one minute. Preferred oral doses of phentolamine mesylatein the formulations of the present invention are from about 5 mg toabout 80 mg.

The present invention is also directed to a vasodilator formulationcomprising in combination, a vasodilator and a chewable tablet.

The present invention is specifically directed to improved methods fortreating male impotence, by administering a vasodilator agent in anamount effective to increase blood flow to the penis wherein erectileability on demand is permitted by oral administration of thevasodilator.

Preferably, the amount of vasodilating agent used in the practice of theinvention for treatment of male impotence is effective to improveerectile ability in from about 1 minute to about 60 minutes followingadministration of the agent.

The invention is also specifically directed to methods for modulatingthe excitation and plateau phases of the female sexual response ondemand by oral administration of an effective amount of vasodilatoragent.

The methods of the present invention are also useful in preparation forsexual intercourse by virtue of the ability to modulate the sexualresponse in both males and females.

The present invention is also directed to the use of a drug havingvasodilator activity for the manufacture of a medicament for oraladministration to modify, on demand, the sexual response in a human andmore particularly to improve erectile ability in response to sexualstimulation. Vasodilator drugs useful for manufacturing the medicamentinclude, but are not limited to, phentolamine mesylate, phentolaminehydrochloride, phenoxybenzamine yohimbine, organic nitrates,thymoxamine, imipramine, verapamil, isoxsuprine, naftidrofuryl,tolazoline, and papaverine.

Numerous other advantages of the present invention will be apparent fromthe following detailed description of the invention including theaccompanying examples and the appended claims.

DETAILED DESCRIPTION

The human sexual response in both the male and female involves a complexinterplay between endocrine, neurological and psychological componentswhich result in certain physiological and anatomical responses in bothmen and women.

While there are obvious differences in the sexual response between menand women, one common aspect of the sexual response is the erectileresponse. The erectile response in both males and females is result ofengorgement of the erectile tissues of the genitalia with blood inresponse to sexual stimulation (physical, psychological, or both).

The vasculature which serves erectile tissue in both men and women issimilar. In particular, in both men and women, the arterial circulationto the erectile tissues of the genitalia derives from the common iliacartery which branches from abdominal aorta. The common iliac arterybifurcates into the internal and external iliac arteries. The internalpudic artery arises from the smaller of two terminal branches of theanterior trunk of the internal iliac artery. In the female, the internalpudic artery branches into the superficial perineal artery whichsupplies the labia pudenda. The internal pudic artery also branches intothe artery of the bulb which supplies the bulbi vestibuli and theerectile tissue of the vagina. The artery of the corpus cavernosum,another branch of the internal pudic artery supplies the cavernous bodyof the clitoris. Still another branch of the internal pudic artery isthe arteria dorsalis clitoridis which supplies the dorsum of theclitoris and terminates in the glans and membranous folds surroundingthe clitoris which correspond to the prepuce of the male.

In the male, the internal pudic artery branches into the dorsal arteryof the penis (which itself branches into a left and right branch) andthe artery of the corpus cavernosum, all of which supply blood to thecorpus cavernosum. The dorsal artery of the penis is analogous to theartery dorsalis clitoridis in the female, while the artery of the corpuscavernosum in the male is analogous to the artery of the same name inthe female.

The male erectile response is regulated by the autonomic nervous systemwhich controls blood flow to the penis via the interaction of peripheralnerves associated with the arterial vessels in and around the corpuscavernosum. In the non-aroused or non-erect state, the arteries servingthe corpus cavernosum are maintained in a relatively constricted state,thereby limiting the blood flow to the corpus cavernosum. However, inthe aroused state, the smooth muscles associated with the arteries relaxunder the influence of catecholamines and blood flow to the corpuscavernosum greatly increases, causing expansion and rigidity of thepenis. Brindley, supra (1986) hypothesizes that smooth musclecontraction opens valves through which blood can flow from the corpuscavernosum into the extracavernosal veins. According to Brindley (1986),when the relevant smooth muscles relax, the valves close diminishingvenous outflow from the corpus cavernosum. When accompanied by increasedarterial blood flow into the corpus cavernosum, this results inengorgement of the corpus cavernosum and an erection.

The pre-orgasmic sexual response in females can be broken down intodistinct phases. Both the excitement phase and the plateau phase involvevasodilation and engorgement (vasocongestion) of the genitalia witharterial blood in a manner analogous to the male erectile response.

The excitement phase of the female sexual response is characterized byvasocongestion in the walls of the vagina which leads to thetransudation of vaginal fluids and vaginal lubrication. Further, theinner one-third of the vaginal barrel expands and the cervix and thebody of the uterus become elevated. This is accompanied by theflattening and elevation of the labia majora and an increase in clitoralsize. [Kolodny et al., Textbook of Sexual Medicine, Little and Brown,Boston, Mass. (1979)].

The plateau phase follows the excitement phase in the female sexualresponse and is characterized by prominent vasocongestion in the outerone-third of the vagina, causing a narrowing of the opening of thevagina and a retraction of the shaft and the glans of the clitorisagainst the symphysis pubis. These responses are also accompanied by amarked vasocongestion of the labia. [Kolodny, supra (1979)].

The vasocongestive aspects of the female sexual response are notrestricted to the genitalia in that areolar engorgement also occurs,sometimes to the extent that it masks the antecedent nipple erectionthat usually accompanies the excitement phase.

The failure of the erectile response in men to the extent that vaginalpenetration and sexual intercourse cannot be achieved is termedimpotence. Impotence has numerous possible causes which can be brokendown into several general classifications. Endocrine related impotencecan result from primary gonadal failure, advanced diabetes mellitus,hypothyroidism, and as one of the secondary sequelae of pituitaryadenoma, idiopathic or acquired hypogonadism, hyperprolactinemia andother endocrine abnormalities.

Chronic systemic illnesses such as cirrhosis, chronic renal failure,malignancies and other systemic diseases can also cause impotence.Neurogenic impotence arising in the central nervous system can be causedby temporal lobe disorders caused by trauma, epilepsy, neoplasms andstroke, intramedullary spinal lesions, paraplegia, and demyelinatingdisorders. Neurogenic causes of impotence arising in the peripheralnervous system include somatic or autonomic neuropathies, pelvicneoplasms, granulomas, trauma, and others. Urologic causes of impotenceinclude complete prostatectomy, local trauma, neoplasms, Peyronie'sdisease, and others. In addition, as discussed above, a significantpercentage of cases of impotence are vasculogenic in nature.

As many as half the cases of male impotence may be psychogenic becausethere is no readily-ascertainable organic cause for the disorder. Evenwhen there appears to be an underlying organic cause of impotence,psychologic factors may play a role in the disorder.

The present invention is designed to modify the circulatory aspects ofthe erectile response on demand using vasoactive agents administered tothe circulation using a rapidly dissolving orally administeredformulation.

A number of vasoactive agents may be used in the practice of the presentinvention based on demonstrated systemic efficacy as vasodilators.Useful vasodilating drugs include those generally classified asα-adrenergic antagonists, sympathomimetic amines and those agents whichexhibit direct relaxation of vascular smooth muscle. Exemplaryα-adrenergic antagonists include phentolamine hydrochloride,phentolamine mesylate, phenoxybenzamine, tolazoline, dibenamine,yohimbine, and others. Phentolamine mesylate is a preferred α-adrenergicagent vasodilator for use preferred practice of the present invention.An exemplary sympathomimetic amine contemplated for use in the method ofthe present invention is nylidrin and use of other sympathomimeticamines having vasodilating activity is also contemplated.

Nicotinic acid (or nicotinyl alcohol) has a direct vasodilating activityuseful in the practice of the present invention. Also contemplated isthe use of papaverine, a non-specific smooth muscle relaxant whichpossesses vasodilating activity and which has been used to treat maleimpotence by direct injection into the corpus cavernosum either alone orin combination with other drugs such as phentolamine. Organic nitratessuch as nitroglycerine and amyl nitrate have pronounced vasodilatingactivity by virtue of their ability to relax vascular smooth muscle andare thus contemplated for use according to the invention. Othervasoactive drugs useful in the practice of the present inventioninclude, without limitation, thymoxamine, imipramine, verapamil,naftidrofuryl, and isoxsuprine.

The formulations also eliminate the need for continuous therapy byproviding a single dose for rapidly improving erectile ability ondemand.

According to the present invention, the vasodilating agent isadministered orally in the form of a rapidly dissolving tabletformulation, a rapidly dissolving chewable tablet formulation,solutions, effervescent formulations, and other orally administeredformulations that permit the rapid introduction of the vasodilatingsubstance to the circulation so as to improve erectile ability within ashort time (on demand) after administration of a single dose of theagent.

Formulations and methods of the present invention are thus moreconvenient and help minimize any side-effects that may arise as a resultof continuous or daily administration of the drugs. In addition, methodsof the present invention allow more spontaneity in sexual activity thanallowed by other methods such as the intracavernosal injection ofvasodilators.

The examples set forth below are intended to be illustrative of thepresent invention and are not intended to limit the scope of theinvention as set out in the appended claims.

Example 1 describes rapidly dissolving formulations for the oraladministration of vasodilating agents. Example 2 describes thebioavailability of phentolamine mesylate when administered using arapidly dissolving oral formulation. Example 3 describes the effect ofthe administration of a rapidly dissolving oral formulation ofphentolamine mesylate on male erectile ability. Example 4 describesother vasoactive agents useful in modulating the human sexual response.Example 5 addresses the practice of the present invention in modulatingthe erectile response in females.

EXAMPLE 1 Rapidly Dissolving Formulations For the Oral Administration ofVasodilating Agents

The present invention is directed to rapidly dissolving orallyadministered formulations for the rapid delivery of vasodilating agentsto the systemic circulation thereby allowing a rapid (on demand) onsetof improved erectile ability in response to sexual stimulation. Theinvention is also directed to other orally administered formulations for"on demand" improvement in erectile ability in response to sexualstimulation including chewable tablets, effervescent formulations,solutions, lozenges, troches, powders, solutions, suspensions,emulsions, or encapsulated powders which can be of the gelatin type orother types.

An exemplary formulation of a rapidly dissolving tablet that includesphentolamine mesylate is set out in Table 1.

                  TABLE 1                                                         ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Phentolamine Mesylate, USP                                                                         40                                                       Silicon Dioxide, NF  8                                                        Stearic Acid, NF     4                                                        Lactose, NF         212                                                       Microcrystalline Cellulose, NF                                                                    120                                                       Croscarmellose Sodium, NF                                                                          16                                                       Total Tablet Weight 400                                                       ______________________________________                                    

The ingredients set out in Table 1 (and those used tablet formulationsset out below) were finely divided and mixed thoroughly before beingcompression formed into tablets having a total weight of about 400 mg.Other methods of mixing and tablet formation will be readily apparent tothose of skill in the art. Physical characteristics of the tabletprepared by this method include an average hardness of 10.7 Kp, anaverage thickness of about 0.20 inches and an average disintegrationtime of about 0.71 minutes.

As shown in Table 1, the disintegrant, croscarmellose sodium NF(available as Ac-Di-Sol®, from FMC Corporation) was used to acceleratethe dissolution of the tablet although other disintegrants such as thosedescribed below may be used to achieve the same effect.

Tablets useful in the practice of the present invention may includeother pharmaceutical excipients, pharmaceutically acceptable salts,carriers, and other substances well known in the art. Buffering agents,flavoring agents, and inert fillers such as lactose, sucrose, cornstarch, binders such as acacia, cornstarch, or gelatin. Disintegrantssuch as potato starch and analgetic acid as well as other commerciallyavailable disintegrants including Explotab® sodium starch glycolate,Polyplasdone XL® crospovidone NF, Starch 1500® pregelatinized starch NF.Gissinger et al., "A Comparative Evaluation of the Properties of SomeTablet Disintegrants", Drug Development and Industrial Pharmacy6(5):511-536 (1980) also describes other disintegrants and methods formeasuring disintegration time of tablets and is incorporated herein byreference. A method for measuring disintegration times of tablets isalso set out in European Pharmacopeia 1980 which is also incorporatedherein by reference. Preferred disintegration times for the practice ofthe present invention are less then about 20 minutes. More preferred aredisintegration times of two minutes or less. Most preferred is adissolution time of less than one minute. Preferred dissolution timesmay vary depending on the parmaco kinetic properties of the vasodilatoragent itself.

Formulations useful in the practice of the present invention may vary solong as the formulation maintains the properties of rapid dissolutionand improved bioavailability of the active ingredient or ingredients.

Another example of a rapidly disintegrating tablet formulation isdescribed in U.S. Pat. No. 5,298,261 to Pebley et al., (the '261 patent)which is incorporated herein by reference. The '261 patent describes arapidly dissolving tablet comprising a drug and a matrix network thathas been vacuum-dried below the equilibrium freezing point of the matrixbut above its collapse temperature. The matrix network set out in the'261 patent preferably includes a gum, a carbohydrate, and the drug.Preferred gums include acacia, guar, xanthin, carrageenan, ortragacanth. Preferred carbohydrates described in the '261 patent includemannitol, dextrose, sucrose, lactose, maltose, maltodextrin, or cornsyrup solids.

Another rapidly dissolving formulation is described in U.S. Pat. No.5,079,018 to Ecanow (the '018 patent) which is incorporated herein byreference. The '018 patent describes a readily dissolvable carrier thatcomprises a drug, an interim skeletal structure of a water soluble,hydratable gel or foam forming material, preferably a proteinaceousmaterial.

The above formulations are given by way of example and other rapidlydissolving formulations will be apparent to those of skill in the art.

EXAMPLE 2 Bioavailability of Phentolamine Mesylate as a RapidlyDissolving, Orally Administered Formulation

Preliminary studies were conducted to compare the bioavailability of asingle 40 mg dose of phentolamine mesylate when administered in the formof an orally administered rapidly dissolving tablet, with thebioavailability of phentolamine mesylate when orally administered in astandard release hard tablet.

Rapidly dissolving tablets containing 40 mg of phentolamine mesylatewere prepared as described in Table 1. Standard release hard tabletscontaining 40 mg of phentolamine mesylate were prepared as follows:

                  TABLE 2                                                         ______________________________________                                        Standard Release Hard Tablet                                                                     mg/tablet                                                  ______________________________________                                        Phentolamine Mesylate, USP                                                                          40                                                      Silicon Dioxide, NF   8                                                       Stearic Acid, NF      4                                                       Dicalcium Phosphate Dibasic, USP                                                                   228                                                      Microcrystalline Cellulose, NF                                                                     120                                                      Total Tablet Weight  400                                                      ______________________________________                                    

Tablets were formed by direct compression. Physical characteristics oftablets prepared according to Table 2 include a hardness of 11.5 Kp,average tablet thickness of 0.16 inches, and an average disintegrationtime of about 26.33 minutes.

In preliminary studies, a single dose of 40 mg of phentolamine either inthe rapidly dissolving tablet formulation or in the standard releasehard tablet were administered to a group of volunteers.

Five (5) ml blood samples were collected from each individual atpre-dose and at 0.25, 0.50, 0.75, 1.00, 1.5 and 2 hours afteradministration of the formulation and the plasma level of phentolaminewas determined using gas chromatography with electron capture detectionas follows.

Phentolamine (CIBA GEIGY AG) and an internal standard, BA11038 (CIBAGEIGY AG) were extracted from alkalinized human heparinized plasma with5% isopropyl alcohol in toluene. The compounds of interest were backextracted from the organic layer with an acid solution (e.g., 0.05 Msulfonic acid), alkalinized again, and extracted with 5% isopropylalcohol in toluene. Organic solvent was then evaporated and the driedextracts were reconstituted with hexane and derivatized withheptafluorobutyryl-imidazole. The extracts were then washed andreconstituted with hexane. Extracts were then analyzed by injection intoa gas chromatograph equipped with a DB-5 wide bore capillary column andan electron capture detector. The linear range of phentolamineconcentration by this method was 5-400 ng/ml and the lower limit ofaccurate quantitation was 5 ng/ml. Levels of phentolamine weredetermined by comparison to a standard curve generated using knownconcentrations of phentolamine in solution processed using the proceduredescribed above.

Table 3 sets out the plasma phentolamine concentration in volunteersreceiving a 40 mg dose of phentolamine mesylate in a standard releasehard tablet formulation shown in Table 2 at various times afteradministration.

                  TABLE 3                                                         ______________________________________                                        Individual and Mean Plasma Phentolamine Concentrations                        (ng/ml) After Administration of 40 mg Phentolamine Mesylate                   in a Standard Release Hard Tablet                                                      0.25   0.50     0.75 1.00   1.50 2.00                                VOLN     hr     hr       hr   hr     hr   hr                                  ______________________________________                                        1        <5.0   <5.0     <5.0 <5.0   <5.0 <5.0                                2        <5.0   <5.0     <5.0 <5.0   <5.0 8.3                                 3        <5.0   <5.0     <5.0 <5.0   <5.0 <5.0                                MEAN     0.0    0.0      0.0  0.0    0.0  2.8                                 STD. DEV.                                                                              0.0    0.0      0.0  0.0    0.0  4.8                                 C.V. (%) 0      0        0    0      0    171                                 S.E.M.   0.0    0.0      0.0  0.0    0.0  2.8                                 N        3      3        3    3      3    3                                   MIN      <5.0   <5.0     <5.0 <5.0   <5.0 <5.0                                MAX      <5.0   <5.0     <5.0 <5.0   <5.0 8.3                                 ______________________________________                                    

As can be seen in Table 3, quantifiable levels of phentolamine weredetected in only one of the three volunteers tested and were detectedonly at 2 hours after administration of the tablet.

However, as can be seen in Table 4 below, when the same volunteers weregiven a 40 mg dose of phentolamine mesylate in the rapidly dissolvingtablet formulation shown in Table 1, quantifiable levels of phentolaminewere detected in plasma as early as 0.25 hours after administration witha peak plasma level occurring between 0.5 hours and 0.75 hours afteradministration while falling below quantifiable levels between 1.5 hoursand 2.0 hours after administration.

                  TABLE 4                                                         ______________________________________                                        Individual and Mean Plasma Phentolamine Concentrations (ng/ml)                After Administration of 40 mg Phentolamine                                    Mesylate in Rapidly Dissolving Tablet                                                  0.25   0.50     0.75 1.00   1.50 2.00                                Volunteer                                                                              hr     hr       hr   hr     hr   hr                                  ______________________________________                                        1        14.0   22.6     17.9 13.7   6.2  <5.0                                2        11.2   15.9     14.7 12.6   6.6  <5.0                                3        13.7   13.2     10.3 9.9    7.2  <5.0                                MEAN     13.0   17.2     14.3 12.1   6.7  0.0                                 STD. DEV.                                                                              1.5    4.8      3.8  2.0    0.5  0.0                                 C.V. (%) 11.5   27.9     26.6 16.5   7.5  0                                   S.E.M.   0.9    2.8      2.2  1.2    0.3  0.0                                 N        3      3        3    3      3    3                                   MIN      11.2   13.2     10.3 9.9    6.2  <5.0                                MAX      14.0   22.6     17.9 13.7   7.2  <5.0                                ______________________________________                                    

In view of the data shown above that demonstrating that the rapidlydissolving oral formulation of phentolamine mesylate allows more rapidabsorption of phentolamine mesylate into the blood stream than thestandard release oral formulations, a more extensive study ofbioavailability of several dosage levels of phentolamine mesylateadministered in the rapidly dissolving oral formulation described above(40 mg phentolamine mesylate) were conducted. The formulations wereprepared as follows:

                  TABLE 5                                                         ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Phentolamine Mesylate, USP                                                                         20                                                       Silicon Dioxide, NF  8                                                        Stearic Acid, NF     4                                                        Lactose, NF         232                                                       Microcrystalline Cellulose, NF                                                                    120                                                       Croscarmellose Sodium, NF                                                                          16                                                       Total Tablet Weight 400                                                       ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Phentolamine Mesylate, USP                                                                         60                                                       Silicon Dioxide, NF  8                                                        Stearic Acid, NF     4                                                        Lactose, NF         192                                                       Microcrystalline Cellulose, NF                                                                    120                                                       Croscarmellose Sodium, NF                                                                          16                                                       Total Tablet Weight 400                                                       ______________________________________                                    

After mixing of the ingredients, tablets were prepared by directcompression. Physical characteristics of the tablets prepared accordingto Tables 5 and 6 were very similar to those described for tabletsprepared according to Table 1.

In this study, seven male subjects were selected based on medicalhistory and physical examination. All patients had an impotence oforganic etiology with a duration of less than 3-4 years.

In this study, subject males were given one of the above-indicatedformulations of phentolamine mesylate in the indicated doses. Fivemilliliters of blood were collected from each patient at pre-dose and0.083, 0.125, 0.167, 0.250, 0.50, 0.750, 1.0, 1.5, 2.0, 4.0, 6.0, and 8hours following the dose and the plasma level of phentolamine wasmeasured as described above.

Tables 7, 8, and 9 show the results of these studies.

Table 7 illustrates the plasma level of phentolamine mesylate afteradministration of a 20 mg dose of drug in the rapidly dissolving oraltablet formulation as shown in Table 5.

                                      TABLE 7                                     __________________________________________________________________________    Individual and Mean Plasma Phentolamine Concentrations (ng/mL)                for Phentolamine Mesylate 20 mg Rapidly Dissolving Tablet                           0.000                                                                            0.083                                                                            0.125                                                                            0.167                                                                            0.250                                                                            0.500                                                                            0.750                                                                            1.000                                                                            1.500                                                                            2.000                                                                            4.000                                                                            6.000                                                                            8.000                               VOLN  hr hr hr hr hr hr hr hr hr hr hr hr hr                                  __________________________________________________________________________    1     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             6.7                                                                              9.6                                                                              11.4                                                                             7.8                                                                              6.2                                                                              <5.0                                                                             <5.0                                                                             <5.0                                2     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             8.1                                                                              6.0                                                                              <5.0                                                                             5.9                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                3     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             9.0                                                                              9.1                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                4     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             7.7                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                5     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             8.2                                                                              6.6                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                6     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             7.1                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                7     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             10.3                                                                             16.7                                                                             10.9                                                                             7.2                                                                              <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                MEAN  0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              2.6                                                                              5.4                                                                              5.1                                                                              4.0                                                                              4.1                                                                              0.9                                                                              0.0                                                                              0.0                                                                              0.0                                 STD. DEV.                                                                           0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              4.6                                                                              6.1                                                                              5.0                                                                              5.1                                                                              3.9                                                                              2.3                                                                              0.0                                                                              0.0                                                                              0.0                                 C.V. (%)                                                                            0  0  0  0  177                                                                              113                                                                              98.0                                                                             128                                                                              95.1                                                                             256                                                                              0  0  0                                   S.E.M.                                                                              0.0                                                                              0.0                                                                              0.0                                                                              0.0                                                                              1.7                                                                              2.3                                                                              1.9                                                                              1.9                                                                              1.5                                                                              0.9                                                                              0.0                                                                              0.0                                                                              0.0                                 N     7  7  7  7  7  7  7  7  7  7  7  7  7                                   MIN   <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                MAX   <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             10.3                                                                             16.7                                                                             10.9                                                                             11.4                                                                             7.8                                                                              6.2                                                                              <5.0                                                                             <5.0                                                                             <5.0                                __________________________________________________________________________

As seen in Table 7, mean plasma phentolamine levels peak at about 5.4ng/ml with the peak occurring between 0.25 hours and 0.50 hours, with asubsequent fall off in phentolamine level beginning between 0.50 hoursand 0.75 hours.

Table 8 illustrates mean plasma levels of phentolamine afteradministration of a 40 mg dose in the rapidly dissolving oralformulation shown in Table 1.

                                      TABLE 8                                     __________________________________________________________________________    Individual and Mean Plasma Phentolamine Concentrations (ng/mL)                for Phentolamine Mesylate 40 mg Tablet                                              0.000                                                                            0.083                                                                            0.125                                                                            0.167                                                                            0.250                                                                            0.500                                                                            0.750                                                                            1.000                                                                            1.500                                                                            2.000                                                                            4.000                                                                            6.000                                                                            8.000                               VOLN  hr hr hr hr hr hr hr hr hr hr hr hr hr                                  __________________________________________________________________________    1     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             8.2                                                                              38.2                                                                             25.9                                                                             16.3                                                                             11.6                                                                             8.7                                                                              6.3                                                                              <5.0                                                                             <5.0                                2     <5.0                                                                             <5.0                                                                             <5.0                                                                             6.1                                                                              13.0                                                                             20.1                                                                             13.5                                                                             10.5                                                                             10.0                                                                             7.7                                                                              <5.0                                                                             <5.0                                                                             <5.0                                3     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             8.0                                                                              20.6                                                                             15.9                                                                             14.3                                                                             13.7                                                                             9.6                                                                              <5.0                                                                             <5.0                                                                             <5.0                                4     <5.0                                                                             <5.0                                                                             5.6                                                                              5.4                                                                              8.2                                                                              11.8                                                                             17.9                                                                             15.3                                                                             10.6                                                                             9.2                                                                              5.3                                                                              <5.0                                                                             <5.0                                5     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             9.7                                                                              9.3                                                                              <5.0                                                                             <5.0                                                                             <5.0                                6     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             11.0                                                                             15.1                                                                             17.0                                                                             11.4                                                                             <5.0                                                                             <5.0                                                                             <5.0                                7     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             6.8                                                                              26.2                                                                             NS 20.0                                                                             14.4                                                                             10.8                                                                             <5.0                                                                             <5.0                                                                             <5.0                                MEAN  0.0                                                                              0.0                                                                              0.8                                                                              1.6                                                                              6.3                                                                              16.7                                                                             14.0                                                                             13.1                                                                             12.4                                                                             9.5                                                                              1.7                                                                              0.0                                                                              0.0                                 STD. DEV.                                                                           0.0                                                                              0.0                                                                              2.1                                                                              2.8                                                                              4.7                                                                              13.9                                                                             8.6                                                                              6.4                                                                              2.7                                                                              1.2                                                                              2.8                                                                              0.0                                                                              0.0                                 C.V. (%)                                                                            0  0  263                                                                              175                                                                              74.6                                                                             83.2                                                                             61.4                                                                             48.9                                                                             21.8                                                                             12.6                                                                             165                                                                              0  0                                   S.E.M.                                                                              0.0                                                                              0.0                                                                              0.8                                                                              1.1                                                                              1.8                                                                              5.3                                                                              3.5                                                                              2.4                                                                              1.0                                                                              0.5                                                                              1.1                                                                              0.0                                                                              0.0                                 N     7  7  7  7  7  7  6  7  7  7  7  7  7                                   MIN   <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             9.7                                                                              7.7                                                                              <5.0                                                                             <5.0                                                                             <5.0                                MAX   <5.0                                                                             <5.0                                                                             5.6                                                                              6.1                                                                              13.0                                                                             38.2                                                                             25.9                                                                             20.0                                                                             17.0                                                                             11.4                                                                             6.3                                                                              <5.0                                                                             <5.0                                __________________________________________________________________________

These data show that the mean plasma levels of phentolamine peak atabout 16.7 ng/ml with the peak occurring at around 0.5 hours afteradministration while quantifiable levels of drug were maintained for aslong as 2 hours after administration with two patients showingquantifiable levels for as long as 4 hours after administration.

Table 9 illustrates individual and mean plasma phentolamineconcentrations in plasma after administration of a 60 mg dose ofphentolamine mesylate in the rapidly dissolving oral formulation shownin Table 6.

                                      TABLE 9                                     __________________________________________________________________________    Individual and Mean Plasma Phentolamine Concentrations (ng/mL)                for Phentolamine Mesylate 60 mg Tablet                                              0.000                                                                            0.083                                                                            0.125                                                                            0.167                                                                            0.250                                                                            0.500                                                                            0.750                                                                            1.000                                                                            1.500                                                                            2.000                                                                            4.000                                                                            6.000                                                                            8.000                               VOLN  hr hr hr hr hr hr hr hr hr hr hr hr hr                                  __________________________________________________________________________    1     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             8.1                                                                              20.1                                                                             15.5                                                                             13.4                                                                             16.3                                                                             18.6                                                                             12.4                                                                             5.3                                                                              <5.0                                2     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             42.2                                                                             41.0                                                                             25.1                                                                             17.2                                                                             13.7                                                                             8.1                                                                              <5.0                                                                             <5.0                                3     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             15.4                                                                             38.2                                                                             43.8                                                                             27.7                                                                             16.3                                                                             7.1                                                                              <5.0                                                                             <5.0                                4     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             13.7                                                                             32.1                                                                             23.5                                                                             14.6                                                                             8.0                                                                              <5.0                                                                             <5.0                                5     <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             20.1                                                                             18.4                                                                             12.2                                                                             10.3                                                                             6.7                                                                              <5.0                                                                             <5.0                                                                             <5.0                                6     <5.0                                                                             <5.0                                                                             <5.0                                                                             5.7                                                                              11.8                                                                             12.8                                                                             21.2                                                                             17.4                                                                             25.2                                                                             13.5                                                                             5.8                                                                              <5.0                                                                             <5.0                                7     <5.0                                                                             <5.0                                                                             <5.0                                                                             5.3                                                                              24.6                                                                             49.7                                                                             46.1                                                                             37.7                                                                             25.3                                                                             16.7                                                                             8.3                                                                              <5.0                                                                             <5.0                                MEAN  0.0                                                                              0.0                                                                              0.0                                                                              1.6                                                                              6.4                                                                              22.9                                                                             27.7                                                                             26.0                                                                             20.8                                                                             14.3                                                                             7.1                                                                              0.8                                                                              0.0                                 STD. DEV.                                                                           0.0                                                                              0.0                                                                              0.0                                                                              2.7                                                                              9.4                                                                              17.3                                                                             13.5                                                                             12.3                                                                             6.3                                                                              3.8                                                                              3.7                                                                              2.0                                                                              0.0                                 C.V. (%)                                                                            0  0  0  169                                                                              147                                                                              75.5                                                                             48.7                                                                             47.3                                                                             30.3                                                                             26.6                                                                             52.1                                                                             250                                                                              0                                   S.E.M.                                                                              0.0                                                                              0.0                                                                              0.0                                                                              1.0                                                                              3.6                                                                              6.5                                                                              5.1                                                                              4.6                                                                              2.4                                                                              1.4                                                                              1.4                                                                              0.8                                                                              0.0                                 N     7  7  7  7  7  7  7  7  7  7  7  7  7                                   MIN   <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             <5.0                                                                             13.7                                                                             12.2                                                                             10.3                                                                             6.7                                                                              <5.0                                                                             <5.0                                                                             <5.0                                MAX   <5.0                                                                             <5.0                                                                             <5.0                                                                             5.7                                                                              24.6                                                                             49.7                                                                             46.1                                                                             43.8                                                                             27.7                                                                             18.6                                                                             12.4                                                                             5.3                                                                              <5.0                                __________________________________________________________________________

The results in Table 9 show that near the plasma levels in patientsreceiving 60 mg of phentolamine in a rapidly dissolving oral formulationpeaked at about 2.27 ng/ml with the peak occurring at around 0.75 hoursafter administration while quantifiable levels of drug remained in theplasma for at least 4 hours after administration.

While the studies described above were conducted using a rapidlydissolving formulation, other formulations that allow rapid absorptionof an active vasodilator agent and corresponding improvement in erectileability are within the scope of the present invention. For example, thepresent invention also includes a chewable tablet formulation shown inTable 10.

                  TABLE 10                                                        ______________________________________                                                         mg/tablet                                                    ______________________________________                                        Phentolamine Mesylate, USP                                                                       40                                                         Silicon Dioxide, NF                                                                              12                                                         Stearic Acid, NF   12                                                         Lactose, NF        100                                                        Sweetrex           348                                                        Aspartame          40                                                         ProSweet            8                                                         Peppermint Flavor #860-172                                                                       40                                                         Total Tablet Weight                                                                              600                                                        ______________________________________                                    

EXAMPLE 3 Effect of the Administration of Rapidly Dissolving OralFormulation of Phentolamine Mesylate on Male Erectile Ability

In order to test the ability of a rapidly dissolving oral formulation ofphentolamine mesylate on erectile ability, a single blind trial wasconducted.

All patients had impotence of organic etiology. Patients were selectedfor inclusion in the trial based medical history and physicalexamination with a duration of impotence of less than 3-4 years. Eachpatient was given two tablets: a rapidly dissolving tablet containing 40mg of phentolamine mesylate (see Table 1), and a placebo tablet lackingphentolamine mesylate.

Patients were asked to take one tablet 20 to 30 minutes beforeattempting coitus. One or more days after using the first tablet, thepatients repeated the process with the second tablet.

Patients were advised not to consume alcohol prior to using the tabletsand were told not to expect erection without sexual stimulation.Patients were told that either tablet might prove beneficial and weretold to report results in terms of erection and vaginal penetration orfailure to achieve an erection sufficient for vaginal penetration.Patients were also asked to report side effects. Results of this studyare illustrated in Table 10.

                  TABLE 11                                                        ______________________________________                                                  Tablet A        Tablet B                                                      (drug)          (placebo)                                           Group       S      U          S    U                                          ______________________________________                                        A           2      2          0    4                                          B           1      3          0    4                                          Total       3      5          0    8                                          ______________________________________                                         S = Erection sufficient for vaginal penetration                               U = Erection Insufficient for vaginal penetration                        

As can be seen in Table 11, 50% of patients in Group A who took therapidly dissolving oral formulation were able to achieve erectionsufficient for vaginal penetration within 30 minutes of administrationof the drug while 33% of the patients in Group B had success. Also, asshown in Table 10, there were no placebo responders.

Although significant success was achieved using a 40 mg dose ofphentolamine mesylate, it is expected that doses ranging from about 5 mgto about 100 mg of phentolamine will be useful in the practice of thepresent invention.

EXAMPLE 4 Vasoactive Agents Useful in Modulating the Human SexualResponse

A number of other vasoactive agents may be used in the practice of thepresent invention based on their demonstrated efficacy as vasodilators.Useful vasodilating drugs include those generally classified asα-adrenergic antagonists, sympathomimetic amines and those agents whichexhibit direct relaxation of vascular smooth muscle.

Exemplary α-adrenergic antagonists include phentolamine hydrochloride,phentolamine mesylate, phenoxybenzamine, tolazoline, dibenamine,yohimbine, and others. Phentolamine mesylate is preferred in thepractice of the present invention. An exemplary sympathomimetic aminecontemplated for use in the method of the present invention is nylidrinalthough other sympathomimetic amines having vasodilating activity arealso comprehended by the invention.

Nicotinic acid (or nicotinyl alcohol) has a direct vasodilating activitywhich is useful in the practice of the present invention. Papaverine isalso non-specific smooth muscle relaxant which has vasodilating activityand has been used to treat male impotence by direct injection into thecorpus cavernosum either alone or in combination with other drugs suchas phentolamine.

Organic nitrates such as nitroglycerine and amyl nitrate also havepronounced vasodilating activity by virtue of their ability to relaxvascular smooth muscle. Other vasoactive drugs of use in the practice ofthe present invention include but are not limited to thymoxamine,imipramine, verapamil, naftidrofuryl, isoxsuprine, and others.

In the practice of the present invention, these vasoactive agents areadministered in rapidly dissolving orally administered formulation orother formulations such as troches, lozenges, chewable tablets,effervescent formulation, powders, solutions, and other formulationsthat provide for rapid delivery of the vasodilating agent to thesystemic circulation and which provide the on demand of advantages ofthe present invention.

Appropriate doses of each vasoactive agents for each route ofadministration are readily determined by those of ordinary skill in theart. By way of illustration, in order to determine the appropriate doseof each of the vasodilating agents of the present invention, one ofordinary skill in the art may use as a starting point, the usualpublished dosage of the vasodilator. The usual oral doses forcommercially available vasodilators can be found in the Physician's DeskReference published annually by Medical Economic Data, Montvale NewJersey, and in the available medical literature.

By way of example, Pavabid® oral papaverine hydrochloride is availablefrom Marion Merrell Dow and is normally administered at 150 mg every 12hours to achieve its vasodilating effects.

The oral dose of Calon® (verapamil hydrochloride) available from Searleis determined by titrating the individual patient with from 120 mg toabout 240 mg of drug every 12 hours, the specific dose depending on theindividual patient's response to the drug.

Yohimbine hydrochloride available as Daytohimbin® (DaytonPharmaceuticals), Yocon® (Palisades Pharmaceuticals), and Yohimex®(Kramer) are all administered orally as 5.4 mg three times a day.

Imipramine hydrochloride is available as Tofranil® from Geigy and isadministered orally 4 times a day for a total dose ranging from 50 mg toabout 150 mg per day.

Imipramine pamoate, also available from Geigy is administered in oralmaintenance doses of 150 mg/day.

Using the established oral dosages as starting points, the optimaldosage for the specific route of administration can be determined bymeasuring baseline arterial blood flow in genital circulation of thepatient prior to administration of the drug using a doppler ultrasoundvelocimeter as described in Zorgniotti et al., PCT/US94/09048. Othermethods such as thermography, plethysmography, radiometric orscintigraphic methods, and other methods well known in the art may alsobe utilized to assess blood flow in the genitalia. Having establishedbase line blood flow, various dosages of the respective vasodilators maybe administered using the formulations encompassed by the presentinvention and their effect on blood flow may be measured. The magnitudeof the increase in blood flow necessary to modulate or enhance thesexual response in humans may vary from individual to individual, but isreadily determined as described in Zorgniotti et al. PCT/US94/09048. Inaddition, individual patients may be titrated with various dosages ofthe respective vasodilators until the optimum dosage is determined.

Vascular flow studies may also be coupled with assessments of sexualresponsiveness as evidenced by the improvement of erectile ability inresponse to sexual stimulation.

EXAMPLE 5 Modulation of the Female Sexual Response

As discussed above, there are striking parallels between the vascularanatomy of male and female genitalia and in the erectile responsefacilitated by this vasculature. In both males and females, the erectileresponse takes place when under physical or psychological stimulation,blood flow to the genitalia increases by virtue of relaxation of smoothmuscles in the arteries serving the genitalia.

The methods and formulations of the present invention may be used toimprove or enhance the erectile response in women whose sexual responseis impaired as evidenced by diminished capacity to produce sufficientvaginal lubrication to facilitate comfortable penile penetration and byother symptoms of impaired sexual responsiveness that may be correlatedwith the erectile response.

As in the case of male sexual response, in the absence of any clinicallydiagnosed dysfunction in the female erectile response, the methods ofthe present invention may be used to enhance the normal female sexualresponse. The "on demand" aspect of the present invention will allow amore rapid response to sexual stimulation along with heightenedsensation associated with excitement and plateau stages of the femalesexual response by virtue of the increased blood flow to the tissues.

In practice, enhancement of the female sexual response using the methodsof the present invention are carried in much the same way as thosedescribed for males as described above.

An effective vasodilating dose of a vasodilating agent is administeredto a woman the formulations of the present invention. The appropriatedoses of the particular vasodilating agent may be readily determinedusing methods described in Example 4. The female response may bemeasured using methods described in Masters, W. H. and Johnson, V. E.,Human Sexual Response, Little, Brown, and Co., Boston (1966) which isincorporated herein by reference. Methods for measuring blood flow,including doppler ultrasonic velocimetry, thermography using for examplean isothermal blood flow transducer, radioscintigraphic methods,photoplethysmography may be used as well as other methods well known inthe art. In addition, measuring the contraction of the distal 1/3 as ischaracteristic of the plateau phase of female sexual response of thevagina may be measured using methods and equipment well known in the artincluding but not limited to strain gauges or other devices formeasuring muscular contraction or muscle tension.

In addition, enhanced sexual response may be measured in a moresubjective manner by simply asking the female subject to describe anychange in sensation brought about by administration of the vasodilatorby the methods of the present invention. Appropriate placebo controlsshould also be conducted to ascertain whether or not the effort isdirectly attributable to the administration of the vasodilator.

Preferred embodiments of the present invention involves theadministration of from about 5 mg to about 80 mg of phentolaminemesylate in a rapidly dissolving oral formulation of the presentinvention from about 1 minute to about 1 hour prior to, and inpreparation for intercourse. However any of the vasodilating agentsincluded within the scope of the present invention may be used.

While this invention has been described by way of preferred embodiments,the examples set out herein are not intended to limit the scope of theinvention which contemplates the use of any pharmacologic vasodilatingdrug capable of absorption into the systemic circulation uponadministration of the drug via an orally administered formulationcapable of improving erectile ability on demand.

I claim:
 1. A composition comprising an orally administrable rapidlydissolving powder, chewable tablet, effervescent tablet, effervescentpowder, encapsulated powder, comprising phentolamine and apharmaceutically acceptable carrier, said composition having adisintegration time of twenty minutes or less.
 2. The compositionaccording to claim 1 wherein the composition has a disintegration timeof from about one minute to about ten minutes.
 3. The compositionaccording to claim 1 wherein the composition has a disintegration timeof less than about one minute.
 4. The composition according to any oneof claim 1, 2 or 3 wherein phentolamine is phentolamine mesylate.
 5. Thecomposition according to claim 4 wherein the composition comprises fromabout 5 mg to about 80 mg phentolamine mesylate.
 6. The compositionaccording to claim 4 wherein the composition comprises about 40 mg ofphentolamine mesylate.
 7. The composition according to claim 4 whereinthe composition comprises 80 mg phentolamine mesylate.
 8. Thecomposition according to any one of claim 1, 2 or 3 wherein phentolamineis phentolamine hydrochloride.
 9. The composition according to claim 8wherein the composition comprises about 5 mg to about 80 mg phentolaminehydrochloride.
 10. The composition according to claim 8 wherein thecomposition comprises about 40 mg phentolamine hydrochloride.
 11. Thecomposition according to claim 8 wherein the composition comprises about80 mg phentolamine hydrochloride.
 12. A composition comprising an orallyadministrable rapidly dissolving tablet comprising 40 mg phentolaminemesylate in a pharmaceutically acceptable carrier, said tablet having adisintegration time of less than 20 minutes.
 13. A compositioncomprising an orally administrable rapidly dissolving tablet comprising80 mg phentolamine mesylate in a pharmaceutically acceptable carrier,said tablet having a disintegration time of less than 20 minutes.
 14. Amethod for improving sexual responsiveness comprising orally ingesting acomposition comprising a rapidly dissolving powder, chewable tablet,effervescent tablet, effervescent powder, encapsulated powder,comprising an amount of phentolamine effective to improve erectileability within one hour after orally ingesting said composition and apharmaceutically acceptable carrier, said composition having adisintegration time of twenty minutes or less.
 15. A method forimproving sexual responsiveness comprising orally ingesting a solutioncomprising phentolamine and a pharmaceutically acceptable carrier. 16.The method of claim 14 wherein said composition has a disintegrationtime of from about one minute to about ten minutes.
 17. The method ofclaim 14 wherein said composition has a disintegration time of less thanabout one minute.
 18. The method of any of claims 14-17 wherein erectileability is improved within 45 minutes after ingesting said composition.19. The method of any of claims 14-17 wherein erectile ability isimproved within 30 minutes after ingesting said composition.
 20. Themethod of any one of claims 14-17 wherein phentolamine is phentolaminemesylate.
 21. The method of claim 20 wherein erectile ability isimproved within 45 minutes after ingesting said composition.
 22. Themethod of claim 20 wherein erectile ability is improved within 30minutes after ingesting said composition.
 23. The method of claim 20wherein said composition comprises from about 5 mg to about 80 mgphentolamine mesylate.
 24. The method of claim 23 wherein erectileability is improved within 45 minutes after ingesting said composition.25. The method of claim 23 wherein erectile ability is improve d within30 minutes after ingesting said composition.
 26. The method of claim 23wherein said composition comprises from about 5 mg to about 80 mgphentolamine hydrochloride.
 27. The method of claim 23 wherein saidcomposition comprises about 40 mg phentolamine hydrochloride.
 28. Themethod of claim 23 wherein said composition comprises about 80 mgphentolamine hydrochloride.
 29. The method of claim 20 wherein saidcomposition comprises about 40 mg phentolamine mesylate.
 30. The methodof claim 20 wherein said composition comprises about 80 mg phentolaminemesylate.
 31. The method of any of claims 23, 29, 30 wherein erectileability is improved within 45 minutes after orally ingesting saidcomposition.
 32. The method of any of claims 23, 29, 30 wherein erectileability is improved within 30 minutes after orally ingesting saidcomposition.
 33. The method of any one of claims 14-17 whereinphentolamine is phentolamine hydrochloride.
 34. The method of any one ofclaims 31-33 wherein erectile ability is improved within 45 minutesafter orally ingesting said composition.
 35. The method of any one ofclaims 31-33 wherein erectile ability is improved within 30 minutesafter orally ingesting said composition.
 36. A method for improvingsexual responsiveness comprising orally ingesting a suspensioncomprising phentolamine and a pharmaceutically acceptable carrier.